Hearing loss is a major health problem that affects more than 28 million Americans; two million persons are profoundly deaf. Approximately 1 in 1,000 infants has profound prelingual deafness and about 40-60% of cases is attributed to genetic causes. Among heritable cases, more than 300 different syndromes have been described, yet syndromic forms account for only ~30% of all genetic cases. Unparalleled genetic heterogeneity is a hallmark of genetic deafness, and over 70 genes have been identified largely within the last decade. Despite the significant role of genetic factors in the etiology of deafness, and the dramatic success that has been achieved in mapping and cloning genes for both syndromic and non-syndromic forms of deafness, much remains to be known about genes involved in the hearing process and the molecular nature of disorders of these genes. In overview, the major goals of this application are to identify and characterize genes involved in hearing using a variety of genetic and genomics based approaches. This knowledge will undoubtedly contribute to better methods for earlier diagnosis, more precise genetic counseling, improved medical treatment, and perhaps, even the prevention of some forms of deafness. The proposed experimental design and methods are: (1) to continue our study of the biology of COCH, an abundantly expressed cochlear gene pathogenetic for the deafness and vestibular disorder DFNA9, using various experimental systems including investigation of a knock-in mouse model for a COCH missense mutation observed in DFNA9 by expression and proteomic analyses, (2) to continue to investigate human cochlear and mouse organ of Corti ESTs using bioinformatics approaches including use of custom cDNA microarrays, and to search for new auditory genes by expression analyses, and 3) to characterize additional cochlear genes selected from chromosomal rearrangements in individuals with hearing impairment. PUBLIC HEALTH RELEVANCE: The importance of this research is the identification and characterization of genes involved in hearing in an effort to enhance our understanding of the normal hearing process and the genetic aberrations that result in hearing impairments. A more complete knowledge of the genes involved in the auditory system will provide a foundation for future diagnosis, management and treatment of hearing loss.